PROJECT SUMMARY/ABSTRACT Hypertension is one of the leading risk factors for cerebrovascular disease and cognitive impairments, especially with aging. Although older hypertensive adults display impaired myogenic response (MR) and autoregulation of cerebral blood flow (CBF), the genes and mechanisms involved and their contribution to hypertension-related dementia are not fully elucidated. This proposal is a direct extension of my R21 application (AG050049) funded by NIA ASG in which we developed animal models to investigate the role of Add3 in mediating cognitive impairments with aging. Our genetic analysis involving the Atherosclerosis Risk in Communities Neurocognitive Study revealed that variants of gamma-adducin (ADD3) are associated with dementia. In animal studies, we genetically mapped a mutation in the Add3 gene in FHH rats that impairs cerebral MR and autoregulation. During the funded R21 period, we generated and characterized Add3 transgenic rats and confirmed that decreased Add3 expression is a driving force for impaired cerebral hemodynamics, which consequently leads to blood-brain barrier (BBB) leakage, inflammation, and ultimately loss of hippocampal neurons and cognitive function upon aging and hypertension. Our new preliminary data demonstrate that downregulation of Add3 damages actin cytoskeletal structure, reduces actin stabilization, and elevates superoxide production in primary cerebral VSMCs isolated from FHH rats. The same structural changes are also observed in glial cells treated with Add3 DsiRNA. In addition, A? protein expression in the brain of FHH rats starts to increase as early as 8 weeks of age. There is mitochondrial damage in the brain surrounding leaky capillaries in hypertensive FHH rats. Mitochondrial respiration and ATP production are compromised in glial cells treated with Add3 DsiRNA. Based on this evidence, we HYPOTHESIZE that reduced Add3 expression uncouples F-actin anchoring to the membrane and enhances aberrant actin polymerization, which impairs CBF autoregulation and promotes development of cognitive impairments in aging-hypertension by attenuating cerebrovascular cell constriction, reducing glial A? clearance, and exacerbating cerebral vascular mitochondrial dysfunction. We will use Add3 gene KO rat on normal SD genetic background and pharmaceutical interventions to determine if enhanced actin polymerization alters MR of cerebral arteries, which could explain impaired CBF autoregulation, BBB leakage, neurodegeneration, and dementia. We will also determine if there is diminished A? clearance and cerebral vascular mitochondrial dysfunction in Add3 KO rats. The results from the proposed studies will establish that aging-hypertension promotes impaired CBF autoregulation, contributing to cognitive deficits. The uncovered mechanisms will address a critical knowledge gap to better understand whether downregulation of ADD3 is a risk factor for development of age- and hypertension-related dementia. This will lay the foundation for discovery of novel biomarkers and drugs that restore CBF autoregulation to prevent the onset and slow the progression of dementia in elderly hypertensive individuals.